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A correction has been published: N Engl J Med 2009;360(22):2379.
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Background Atrial fibrillation is the most common cardiac arrhythmia, and no current therapy is ideal for control of this condition. Experimental studies suggest that angiotensin II–receptor blockers (ARBs) can influence atrial remodeling, and some clinical studies suggest that they may prevent atrial fibrillation.
Methods We conducted a large, randomized, prospective, placebo-controlled, multicenter trial to test whether the ARB valsartan could reduce the recurrence of atrial fibrillation. We enrolled patients who were in sinus rhythm but had had either two or more documented episodes of atrial fibrillation in the previous 6 months or successful cardioversion for atrial fibrillation in the previous 2 weeks. To be eligible, patients also had to have underlying cardiovascular disease, diabetes, or left atrial enlargement. Patients were randomly assigned to receive valsartan or placebo. The two primary end points were the time to a first recurrence of atrial fibrillation and the proportion of patients who had more than one recurrence of atrial fibrillation over the course of 1 year.
Results A total of 1442 patients were enrolled in the study. Atrial fibrillation recurred in 371 of the 722 patients (51.4%) in the valsartan group, as compared with 375 of 720 (52.1%) in the placebo group (adjusted hazard ratio, 0.97; 96% confidence interval [CI], 0.83 to 1.14; P=0.73). More than one episode of atrial fibrillation occurred in 194 of 722 patients (26.9%) in the valsartan group and in 201 of 720 (27.9%) in the placebo group (adjusted odds ratio, 0.89; 99% CI, 0.64 to 1.23; P=0.34). The results were similar in all predefined subgroups of patients, including those who were not receiving angiotensin-converting–enzyme inhibitors.
Conclusions Treatment with valsartan was not associated with a reduction in the incidence of recurrent atrial fibrillation. (ClinicalTrials.gov number, NCT00376272
[ClinicalTrials.gov]
.)
Some studies have shown that the recurrence of atrial fibrillation after cardioversion may be partially related to a biologic phenomenon known as remodeling, in which the electrical, mechanical, and structural properties of atrial tissue and cardiac cells are progressively and irreversibly altered, creating a more favorable substrate for atrial fibrillation.11,12,13 The renin–angiotensin–aldosterone system plays a role in atrial remodeling. In animal models of atrial fibrillation, blockade of the renin–angiotensin–aldosterone system with the use of an angiotensin-converting–enzyme (ACE) inhibitor or an angiotensin II–receptor blocker (ARB) has been shown to favorably affect electrical and structural remodeling of the atrium.14,15,16,17
Several clinical studies have suggested that ACE inhibitors or ARBs may have a beneficial effect on either new-onset atrial fibrillation (i.e., primary prevention) or recurrent atrial fibrillation (i.e., secondary prevention). However, in those studies, either atrial fibrillation was assessed as an ancillary variable18,19,20,21,22,23,24 or it was the main end point but the study was too small to definitively establish an effect on the incidence or recurrence of atrial fibrillation.25,26,27,28 Published meta-analyses have reached contrasting conclusions on the effects of inhibitors of the renin–angiotensin–aldosterone system.29,30 We conducted the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico–Atrial Fibrillation (GISSI-AF) trial to assess whether the addition of the ARB valsartan to established therapies could reduce the rate of recurrence of atrial fibrillation in patients with a history of that arrhythmia.
Methods
Study Design
The rationale and the design of this study have been described previously.31 The GISSI-AF study was a prospective, multicenter, randomized, double-blind, placebo-controlled trial. It was designed and supervised by the steering committee (see the Appendix) and approved by the ethics committee at each participating center. Funding was provided by Novartis, which had no role in the design or conduct of the trial; the collection, analysis, or interpretation of the data; or the writing of the report. The authors vouch for the accuracy and completeness of the data and the analysis.
Patients
Patients of either sex were eligible for inclusion in the study if they were at least 40 years of age and had had either two or more episodes of symptomatic atrial fibrillation (as documented on an electrocardiogram) in the previous 6 months or successful cardioversion (electrical or pharmacologic) for atrial fibrillation between 14 days and 48 hours before randomization. All patients had to have been in sinus rhythm for at least 2 days before randomization. In addition, patients had to have at least one of the following conditions: heart failure or a documented history of left ventricular dysfunction (defined as an ejection fraction of less than 40%); a history of hypertension for 6 months or more, with or without left ventricular hypertrophy; type 2 diabetes; a history of stroke or peripheral artery disease; a history of coronary artery disease; or atrial fibrillation without coexisting cardiovascular conditions but with left atrial dilatation (defined as a left atrial diameter of 45 mm or greater in men or 40 mm or greater in women).
Patients were excluded if they required treatment with ARBs for another indication; had contraindications to ARBs; had recently (within the previous 6 weeks) had an acute myocardial infarction, coronary bypass operation, or percutaneous coronary intervention; had clinically significant valvular disease; had thyroid dysfunction; or were scheduled to undergo catheter ablation or implantation of a pacemaker or defibrillator.
All participants had to have been on a stable regimen of treatment for atrial fibrillation and for any underlying cardiovascular disorders for at least 1 month before enrollment. Patients were allowed to continue all previously prescribed treatments for these conditions (including ACE inhibitors, amiodarone, and beta-blockers). All eligible patients provided written informed consent before enrollment.
Randomization and Study Treatment
Eligible patients were randomly assigned to either valsartan or matching placebo by means of a computerized, telephone randomization system, with the group assignments concealed. Randomization was based on stratification according to site, with blocks of four patients per site. The study drug was initiated at a dose of 80 mg daily for 2 weeks and was then increased to 160 mg daily for another 2 weeks. At the 4-week visit, the dose was increased to 320 mg daily, and this regimen was continued until the end of the follow-up period at week 52.
Upward adjustment of the dose of the study medication was required for all patients unless they presented with a blood pressure below 110/65 mm Hg or symptomatic hypotension. If a patient could not tolerate a daily dose of 160 mg, the dose was reduced to 80 mg, and attempts were subsequently made to increase the dose again. If the patient could not tolerate a dose of at least 160 mg of the study drug within 2 months after enrollment, the study drug was withdrawn.
Follow-up
Study visits were scheduled at weeks 2, 4, 8, 24, and 52, with the follow-up period concluding at 1 year. A routine clinical examination, including electrocardiography and laboratory testing, was performed at each study visit. To increase the likelihood that atrial fibrillation could be detected, all patients were provided with a transtelephonic monitoring device (Cardiobios 1, Telbios). The patients were asked to activate this device, which would transmit a 30-second electrocardiogram to both the coordinating center and the responsible physician, if symptoms occurred and at least once a week whether or not symptoms occurred. If a recurrence of atrial fibrillation was detected, the patient was asked to come in for an office visit to confirm the findings.
Study End Points
The study was designed with two primary end points: the time to the first recurrence of atrial fibrillation and the proportion of patients who had more than one episode of atrial fibrillation over the 1-year follow-up period. Secondary end points included the total number of episodes of atrial fibrillation per patient, hospitalization for any reason and hospitalization for a cardiovascular event, the composite of death and thromboembolic events, the number of patients in sinus rhythm at the time of each study visit, the duration of and ventricular rate at the first recurrence of atrial fibrillation, and a safety profile. A predefined analysis of the effects of valsartan as compared with placebo on the recurrence of atrial fibrillation was also performed for patients who were in sinus rhythm 15 days after study entry, with the aim of assessing the effect of valsartan after the exclusion of early recurrences of atrial fibrillation. A similar post hoc analysis included patients who were in sinus rhythm at week 8, by which time it was expected that patients would be receiving the target dose of valsartan. An independent end-point committee adjudicated all reports of primary end points, deaths, and hospitalizations.
Statistical Analysis
The estimated sample size was based on the time to the first recurrence of atrial fibrillation. We calculated that for the study to have 88% power to detect a 17.6% relative difference between the valsartan and placebo groups, there would have to be 599 events, assuming an event rate in the placebo group of 50% at 1 year (which corresponds to a yearly hazard rate of 69%) and a withdrawal rate of 15%. On the basis of these calculations, we planned to enroll 1402 patients.
All analyses were performed in the intention-to-treat population. Comparisons of the first primary end point (time to the first recurrence of atrial fibrillation) between the treatment and placebo groups were performed with the use of a log-rank test. We estimated the size of the effect by calculating hazard ratios with the use of a Cox proportional-hazards model. In a further analysis, we included as covariates all the baseline clinical characteristics that were assessed in the study patients. For the second primary end point (the proportion of patients with more than one recurrence of atrial fibrillation), we assessed the treatment effect by using a logistic-regression model to calculate odds ratios, with and without adjustment for all baseline covariates.
We adjusted the overall significance level of 0.05 to account for the inclusion of two primary end points. The first (time to the first recurrence of atrial fibrillation) was tested at a two-sided significance level of 0.04, and the second (proportion of patients with more than one episode of atrial fibrillation), at a two-sided significance level of 0.01. Thus, confidence intervals of 96% and 99% were calculated for the first and the second primary end points, respectively.
We also calculated hazard ratios with 95% confidence intervals, using the Cox regression model to assess the effect of valsartan on the secondary end points and in the prespecified subgroups. For the between-group comparisons of those secondary end points that were expressed as proportions or mean values, we used a chi-square test or t-test. We performed Cox analyses of the primary outcome to test for an unfavorable outcome in prespecified subgroups by fitting a Cox model with one term representing the treatment group, one term representing the covariate of interest, and an interaction term to test for heterogeneity of the effect of valsartan. Changes in systolic blood pressure were analyzed by means of analysis of variance, with adjustment for baseline values, and were reported as least-square means ±SE.
The reported P values are two-sided and not adjusted for multiple testing. All analyses were conducted with SAS software, version 9.2 (SAS Institute).
Results
Patients
From November 2004 through January 2007, we enrolled 1442 patients at 114 centers; 722 patients were randomly assigned to the valsartan group, and 720 to the placebo group. There were no clinically relevant differences between the two groups in baseline characteristics (Table 1), except for a higher prevalence of coronary artery disease and peripheral arterial disease in the valsartan group than in the placebo group. A total of 85.4% of the patients had a history of hypertension, 14.6% had diabetes, and 7.9% had heart failure, left ventricular dysfunction, or both. At the time of randomization, 34.7% of the patients were receiving amiodarone, 57.0% were receiving ACE inhibitors, 30.2% were receiving beta-blockers, and 56.5% were receiving anticoagulant drugs (Table 1).
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By 8 weeks, the least-square mean systolic blood pressure was reduced by 3.91±0.60 mm Hg in the valsartan group and by 1.07±0.60 mm Hg in the placebo group (P<0.001). By the end of the study, the reductions were 4.13±0.63 mm Hg in the valsartan group and 1.96±0.62 mm Hg in the placebo group (P=0.01). The mean heart rate was unchanged from baseline values at 8 weeks and at the end of the study (data not shown). The overall median duration of follow-up was 365 days (interquartile range, 359 to 372). We had follow-up data on survival for all the patients and follow-up data on the first recurrence of atrial fibrillation for almost all the patients (95.5%). More than 80% of expected transtelephonic recordings were actually transmitted.
Primary End Points
At 1 year, 51.4% of the patients (371 of 722) in the valsartan group and 52.1% (375 of 720) in the placebo group had had a recurrence of atrial fibrillation (hazard ratio, 0.98; 96% confidence interval [CI], 0.85 to 1.14; P=0.83) (Figure 1A). After adjustment for all baseline variables reported in Table 1, the adjusted hazard ratio was 0.97 (96% CI, 0.83 to 1.14; P=0.73). Overall, the median times from randomization to the first recurrence of atrial fibrillation were 295 days in the valsartan group and 271 days in the placebo group.
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Secondary Analyses and End Points
Among the 1255 patients who were in sinus rhythm 15 days after study entry, there was no significant difference between the valsartan and placebo groups with respect to the rates of recurrence of atrial fibrillation (47.7% and 48.4%, respectively; hazard ratio, 0.96; 96% CI, 0.81 to 1.13; P=0.59) (Figure 1B). Similar results were obtained from a post hoc analysis of data from the 1254 patients who were in sinus rhythm at week 8, by which time the patients would have been receiving the target dose of valsartan (rate of recurrence, 42.7% in the valsartan group and 44.0% in the placebo group; hazard ratio, 0.96; 96% CI, 0.80 to 1.14; P=0.62). We did not observe significant differences in any of the secondary end points (Table 2), with the exception of thromboembolic events, which occurred in 10 patients in the valsartan group as compared with 2 in the placebo group (hazard ratio, 5.06; 95% CI, 1.11 to 23.11; P=0.04).
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Subgroup Analyses
Hazard ratios for the first recurrence of atrial fibrillation were similar in all predefined subgroups of patients (Figure 2). A nonsignificant trend toward a lower incidence of recurrence of atrial fibrillation was apparent in the valsartan group among the 114 patients who presented with heart failure or left ventricular dysfunction (hazard ratio, 0.81; 95% CI, 0.48 to 1.35; P=0.41).
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The study drug was permanently discontinued in 107 (14.8%) of the patients in the valsartan group and 76 (10.6%) of those in the placebo group (P=0.02). Of these discontinuations, 26 in the valsartan group and 12 in the placebo group were attributed to adverse drug reactions (Table 3). Serious adverse reactions occurred in two patients in the valsartan group (severe hypotension in one patient and renal dysfunction plus hyperkalemia in the other). The proportion of patients who had at least one doubling of the serum creatinine level or who had a serum creatinine level that was higher than 3.5 mg per deciliter (309.4 µmol per liter) during the follow-up period was 0.7% in the valsartan group and 0.9% in the placebo group (P=0.77). The proportion of patients in whom at least one measurement of the serum potassium level was higher than 5.5 mmol per liter during the follow-up period was 5.6% in the valsartan group and 2.4% in the placebo group (P=0.002).
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In the GISSI-AF trial, we tested the effect of an ARB, valsartan, on the recurrence of atrial fibrillation in patients who had a history of atrial fibrillation associated with cardiovascular disease, diabetes, or left atrial enlargement. In these patients, the addition of valsartan to established therapies for atrial fibrillation and for coexisting cardiovascular conditions did not reduce the risk of either a first recurrence or multiple recurrences of atrial fibrillation. These results were consistent across all predefined subgroups. Our findings do not support the original hypothesis of a beneficial role of blockers of the renin–angiotensin–aldosterone system in the prevention of recurrent atrial fibrillation.
Only four previously published studies, in which a total of 665 patients were enrolled, specifically evaluated the role of ARBs in the secondary prevention of atrial fibrillation.25,26,27,28 The results of three of these studies suggested a beneficial effect; in all three of these trials, amiodarone was given to all patients as part of the trial protocol.25,26,27 In contrast, in the subgroup of patients treated with amiodarone in our trial, valsartan did not have a significant beneficial effect.
Our trial did not address the efficacy of agents that block the renin–angiotensin–aldosterone system for the primary prevention of atrial fibrillation. Previous trials and meta-analyses have suggested a more pronounced effect of these agents when they are used for primary prevention,19,20,21,22,23,24,29,30 perhaps because of a beneficial influence on the pathophysiological substrate of atrial fibrillation (i.e., structural or electrical remodeling, or both) before the occurrence of irreversible atrial remodeling. We also did not evaluate the efficacy of ACE-inhibitor therapy, which has been reported to be similar to the efficacy of ARB therapy.29,30
One limitation of many large clinical trials in which the occurrence of atrial fibrillation is not a primary end point is the method used to detect recurrences of atrial fibrillation. Such trials often rely on the results of electrocardiography performed at scheduled office visits or on the patient's report of symptoms (as in the Losartan Intervention for Endpoint Reduction in Hypertension [LIFE], Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity [CHARM], and Valsartan Antihypertensive Long-term Use Evaluation [VALUE] trials).21,23,24 As a result, these trials tend to show lower rates of detection of atrial fibrillation than trials, like ours, that use frequent transtelephonic monitoring.
One limitation of our trial is the relatively short duration (1 year) of clinical follow-up. Some of the large trials mentioned above (LIFE, CHARM, and VALUE) had mean follow-up intervals that were longer than 3 years. The time required for the putative effects of ARBs on atrial remodeling is not well defined. However, we did not detect even a modest trend in favor of valsartan therapy during the course of our trial, suggesting that such an effect would not be anticipated with a longer follow-up period.
Conversely, it seems unlikely that the expected benefit of ARB therapy would occur within the first few days of starting treatment. Early recurrences of atrial fibrillation after cardioversion are probably due to short-term electrical remodeling of atria,32 which tends to normalize within days or weeks if sinus rhythm is again restored. For this reason, we planned a secondary analysis that was limited to data on patients who were in sinus rhythm at the first follow-up visit, on day 15. This analysis did not show any effect of valsartan on the recurrence of atrial fibrillation. Similar results were obtained from a post hoc analysis of data from patients who were in sinus rhythm at week 8, to account for the time needed to reach the target dose of valsartan.
The significant excess of thromboembolic events in the valsartan group was unexpected, and we believe that this result may be a chance finding. Of note, the rate of thromboembolic events in the placebo group in our trial was much lower than expected and was lower than previously reported rates in similar patient populations.33,34
In conclusion, we evaluated the potential benefit of adding 320 mg of valsartan daily to standard therapy in patients who had a history of atrial fibrillation associated with cardiovascular disease, diabetes, or left atrial enlargement. At 1 year, we found no significant reduction in the incidence of recurrent atrial fibrillation among patients receiving valsartan as compared with those receiving placebo.
The GISSI Studies are supported by Associazione Nazionale Medici Cardiologi Ospedalieri and by Istituto di Ricerche Farmacologiche Mario Negri.
Dr. Maggioni reports receiving research support and lecture fees from Novartis; Drs. Disertori and Di Pasquale, lecture fees from Novartis; Drs. Franzosi, Lucci, Barlera, Staszewsky, and Tognoni, institutional research support from Novartis; and Dr. Latini, research support and lecture and consulting fees from Novartis. Drs. Latini and Maggioni are listed as coinventors on a patent application for the therapeutic use of valsartan in atrial fibrillation. No other potential conflict of interest relevant to this article was reported.
We thank the participants in the study and the cardiologists, nurses, ethics committee members, and administrative staff in hospitals who assisted in the conduct of the study.
Source Information
The members of the writing committee (Marcello Disertori, M.D., Department of Cardiology, Santa Chiara Hospital, Trento; Roberto Latini, M.D., Simona Barlera, M.Sci., Maria Grazia Franzosi, Pharm.D., and Lidia Staszewsky, M.D., Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche Mario Negri, Milan; Aldo Pietro Maggioni, M.D., and Donata Lucci, M.Sci., Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence; Giuseppe Di Pasquale, M.D., Cardiology Unit, Maggiore Hospital, Bologna; and Gianni Tognoni, M.D., Consorzio Mario Negri Sud, S. Maria Imbaro, Chieti — all in Italy) assume responsibility for the overall content and integrity of the article.
This article (10.1056/NEJMoa0805710) was updated on May 27, 2009, at NEJM.org.
Address reprint requests to Dr. Maggioni at the GISSI-AF Coordinating Center, ANMCO Research Center, Via La Marmora, 34, 50121 Florence, Italy, or at gissiaf{at}anmco.it.
References
Members of the GISSI-AF study group are as follows: Writing Committee — M. Disertori, R. Latini, A.P. Maggioni, S. Barlera, G. Di Pasquale, M.G. Franzosi, D. Lucci, L. Staszewsky, G. Tognoni; Steering Committee — M. Disertori (chair), R. Latini (cochair), G. Di Pasquale, M.G. Franzosi, A.P. Maggioni, L. Staszewsky, P. Delise, G. Tognoni, (F. Bertocchi and G. Maiocchi, nonvoting members); Data and Safety Monitoring Board — E. Geraci (chair), E. Correale, F. Lombardi, A. Mugelli, R. Urso; Clinical End-point Committee — S. Scardi (chair), G. Fabbri (coordinator), B. Bartolomei (secretary), G. Barbato, E. Carbonieri, S. Ciricugno, F. Cosmi, C. Pratola, M.G. Rossi, L. Sciarra, P. Zeni; Clinical Monitoring — M. Ceseri, A. Atzori, F. Bambi, M. Baviera, F. Bianchini, E. Fenicia, M. Gianfriddo, G. Lonardo, A. Luise, R. Nota, M.E. Orlando, R. Petrolo, C. Pierattini, V. Pierota, A. Ragno, C. Serio, A. Tafi, E. Tellaroli; Core Laboratories — S. Masson, R. Latini, T. Vago (Biomarkers); L. Staszewsky, S. Gramenzi (Echocardiography); F. Orso, I. Suliman (Electrocardiography); Database Management and Statistics — E. Nicolis, C. Casola, S. Barlera, D. Dall'Osso, M. Gorini, D. Lucci; Regulatory, Administrative, and Secretariat — E. Bianchini, S. Cabiddu, I. Cangioli, A. Carnaghi, M.L. Cipressa, L. Cipressa, L. Galbiati, A. Lorimer, P. Priami; Participating Centers and Investigators — Switzerland: Lugano (T. Moccetti, M.G. Rossi, F. Vaghi), Italy: Piemonte: Asti (A.F.L. Capello), Cuneo (G. Rossetti, E. Viada, L. Morena), Saluzzo (M. Delucchi, S.G. Reynaud, P. Allemano), Torino Valdese (N. Massobrio), Lombardia: Bergamo (A. Gavazzi, F. Taddei), Brescia (D.A. Mor), Chiari (F. Bortolini, M. Lorini), Crema (G. Inama, O. Durin), Cremona (S. Pirelli, A. Spotti, R. Procopio), Giussano (D. Cuzzucrea, G. Gentile), Milano San Raffaele (A. Margonato, G. Bassanelli), Pavia San Matteo (L. Tavazzi, M.P. Buzzi, R. Rordorf), Pavia Fondazione Salvatore Maugeri (A. Gualco, C. Opasich), Rozzano (E. Gronda, L. Genovese), Sesto San Giovanni (R. Mattioli, F. Donatelli), Varese (J.A. Salerno Uriarte), P.A. Bolzano: Bolzano (W. Rauhe), P.A. Trento: Cles (C. Bertagnolli, S. Canestrini), Trento Villa Bianca (C. Stefenelli, G. Cioffi), Trento Santa Chiara (M. Disertori, P. Zeni, C. Giovanelli), Veneto: Bovolone (G. Rigatelli, S. Boni, A. Pasini), Conegliano Santa Maria dei Battuti (N. Sitta), Conegliano Veneto De Gironcoli (A. Sacchetta, L. Borgese, R. Sciascia), Este (L. Targa), Mestre (A. Raviele, M. Madalosso), Mirano (E. Bertaglia, F.C. Zoppo), Porto Viro (M. Capanna, R. Fiorencis), Rovigo (E. Baracca), San Bonifacio (R. Rossi, E. Carbonieri, I. Rossi), Villafranca di Verona (R. Trappolin), Friuli Venezia Giulia: Monfalcone (T. Morgera, E. Barducci), Palmanova (M.G. Baldin, G. Gobbo), Pordenone (F. Zardo, E. Hrovatin), San Daniele del Friuli (L. Mos, O. Vriz), Trieste Az. Ospedaliera-Universitaria Ospedali Riuniti (G. Sinagra, A. Aleksova), Trieste Az. Servizi Sanitari n. 1 Triestina (S. Scardi, C. Mazzone), Udine (C. Fresco), Liguria: Genova-Sampierdarena (P. Rubartelli, L.A. Moroni), Genova-Voltri (A. Camerieri), Imperia (M. Piana), Pietra Ligure (R. Mureddu), Sarzana-Loc. S. Caterina (D. Bertoli, R. Petacchi), Emilia Romagna: Bentivoglio (L.G. Pancaldi, L. Gabrieli), Bologna Bellaria (S. Urbinati, C. Pedone), Bologna Maggiore (G. Di Pasquale, M. Di Niro, A. Brunelli), Cotignola (S. Bosi, S. Censi), Ferrara (C. Pratola), Fidenza (P. Moruzzi, P. Pastori), Modena (M.G. Modena, V. Malavasi), Rimini (M. Mezzetti), Sassuolo (F. Melandri), Toscana: Bagno a Ripoli (A. Zuppiroli, A. Fazi), Cecina (R. Testa, E. Venturini, F. Mazzinghi), Cortona (F. Cosmi, D. Cosmi), Firenze Nuovo Osp. S Giovanni di Dio (G.M. Santoro, C. Minneci), Livorno (M. Galli, L. Paperini), Lucca (F.M. Bovenzi, L. Cortigiani), Umbria: Città di Castello (M. Cocchieri, D. Severini, G.M. Arcuri), Foligno (G. Bagliani), Terni (M. Bernardinangeli, G. Proietti, G. Proietti), Marche: Pesaro (P. Bocconcelli, A. Pierantozzi), Lazio: Albano Laziale (F. Monti, L. Giamundo), Formia (P. Tancredi, E. Rossini), Roma Centro Traumatologico Ortopedico (C. Bianchi), Roma San Camillo, Cardiologia Riabilitativa e Preventiva (F. Bettiol), Roma San Camillo, Cardiologia I (E. Giovannini, M.S. Fera), Roma San Filippo Neri (M. Santini, L. Bianconi), Roma San Giovanni (A. Boccanelli, P. Morosetti), Roma Sant'Andrea (M. Volpe, C. Facciolo), Abruzzo: Penne (A. Vacri, F. Romanazzi), Teramo (C. Napoletano, L.L. Piccioni), Campania: Avellino (F. Candelmo), Aversa (G. De Marco, M.R. Arnese), Caserta (A. Vetrano), Giugliano in Campania (D. Prinzi, P. De Rosa), Mercato San Severino (V. Capuano, S. Torre), Napoli Azienda Ospedaliera Monaldi (A. D'Onofrio, E. Ammendola), Napoli Policlinico Universitario Federico II (M. Chiariello, P. Perrone Filardi), Piedimonte Matese (R. Battista, A. De Fusco), Pozzuoli (U. Molero), San Felice a Cancello (A. Iervoglini, S. Stefanelli), Santa Maria Capua Vetere (L. Fattore, B. Bosco), Vallo della Lucania (A. Liguori, G. Padula), Puglia: Bari Ospedale Consorziale Policlinico (I. De Luca, M. Sorino, P. Colonna), Bari-Carbonara (C. D'Agostino, O. Pierfelice), Casarano (G. Pettinati, A. Muscella), Scorrano (E. De Lorenzi, M. Falco), Taranto Villa Verde (C. Giannattasio), Taranto Santissima Annunziata (N. Baldi), Basilicata: Matera (M.A. Clemente), Policoro (B. D'Alessandro, L. Truncellito), Calabria: Catanzaro Pugliese (F. Arabia, V.A. Ciconte), Catanzaro Germaneto (F. Perticone, C. Ruberto), Cosenza Santissima Annunziata (A. Buffon, C. Tomaselli), Cosenza Mariano Santo (F. De Rosa, S. Mazza), Crotone (G. Zampaglione, A.M. Pirozzi), Lamezia Terme (A. Butera, M. Levato), Paola (D. Musacchio), Polistena (R.M. Polimeni, V. Lacquaniti), Reggio Calabria (G. Pulitanò, A. Ruggeri), Rogliano (A. Provenzano), San Marco Argentano (O. Cuccurullo), Scilla (M. Musolino, A. Marrari), Soriano Calabro (L. Anastasio, M. Schiavello), Vibo Valentia (M.G.A. Comito), Sicilia: Catania (M.M. Gulizia, G.M. Francese), Milazzo (L. Vasquez, C. Coppolino), Nicosia (A. Casale, G. D'Urso), Palermo Civico e Benfratelli (G. Oliva, U. Giordano, S. Andolina), Palermo Villa Sofia (N. Sanfilippo, F. Ingrillì), Palermo Buccheri La Ferla (S. Accardo), Palermo Cervello (S. Grasso, L. Buffa), Sardegna: Cagliari Brotzu (E. Serra).
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Related Letters:
Valsartan and Recurrent Atrial Fibrillation
Smit M. D., Van Gelder I. C., Tomoda H., Disertori M., Latini R., Maggioni A. P., the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico–Atrial Fibrillation (GISSI-AF) Investigators
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N Engl J Med 2009;
361:532-533, Jul 30, 2009.
Correspondence
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